Self-Assembled Responsive Bilayered Vesicles with Adjustable Oxidative Stress for Enhanced Cancer Imaging and Therapy.

In the present study, we report the development of magnetic-plasmonic bilayer vesicles assembled from iron oxide-gold Janus nanoparticles (Fe3O4-Au JNPs) for reactive oxygen species (ROS) enhanced chemotherapy. The amphiphilic Fe3O4-Au JNPs were grafted with poly(ethylene glycol) (PEG) on the Au surface and ROS-generating poly(lipid hydroperoxide) (PLHP) on the Fe3O4 surface, respectively, which were then assembled into vesicles containing two closely attached Fe3O4-Au NPs layers in opposite directions. The self-assembly mechanism of the bilayered vesicles was elucidated by performing a series of numerical simulations. The enhanced optical properties of the bilayered vesicles were verified by the calculated results and experimental data. The vesicles exhibited enhanced T2 relaxivity and photoacoustic properties over single JNPs due to the interparticle magnetic dipole interaction and plasmonic coupling. In particular, the vesicles are pH responsive and disassemble into single JNPs in the acidic tumor environment, activating an intracellular biochemical reaction between the grafted PLHP and released ferrous ions (Fe2+) from Fe3O4 NPs, resulting in highly efficient local ROS generation and increased intracellular oxidative stress. In combination with the release of doxorubicin (DOX), the vesicles combine ROS-mediated cytotoxicity and DOX-induced chemotherapy, leading to greatly improved therapeutic efficacy than monotherapies. High tumor accumulation efficiency and fast vesicle clearance from the body were also confirmed by positron emission tomography (PET) imaging of radioisotope 64Cu-labeled vesicles.

Gadolinium Metallofullerene-Based Activatable Contrast Agent for Tumor Signal Amplification and Monitoring of Drug Release.

Activatable imaging probes are promising to achieve increased signal-to-noise ratio for accurate tumor diagnosis and treatment monitoring. Magnetic resonance imaging (MRI) is a noninvasive imaging technique with excellent anatomic spatial resolution and unlimited tissue penetration depth. However, most of the activatable MRI contrast agents suffer from metal ion-associated potential long-term toxicity, which may limit their bioapplications and clinical translation. Herein, an activatable MRI agent with efficient MRI performance and high safety is developed for drug (doxorubicin) loading and tumor signal amplification. The agent is based on pH-responsive polymer and gadolinium metallofullerene (GMF). This GMF-based contrast agent shows high relaxivity and low risk of gadolinium ion release. At physiological pH, both GMF and drug molecules are encapsulated into the hydrophobic core of nanoparticles formed by the pH-responsive polymer and shielded from the aqueous environment, resulting in relatively low longitudinal relativity and slow drug release. However, in acidic tumor microenvironment, the hydrophobic-to-hydrophilic conversion of the pH-responsive polymer leads to amplified MR signal and rapid drug release simultaneously. These results suggest that the prepared activatable MRI contrast agent holds great promise for tumor detection and monitoring of drug release.

Synchronous Chemoradiation Nanovesicles by X-Ray Triggered Cascade of Drug Release.

The approach of concurrent-to-synchronous chemoradiation has now been advanced by well-designed nanovesicles that permit X-ray irradiation-triggered instant drug release. The nanovesicles consist of Au nanoparticles tethered with irradiation labile linoleic acid hydroperoxide (LAHP) molecules and oxidation-responsive poly(propylene sulfide)-poly(ethylene glycol) (PPS-PEG) polymers, where DOX were loaded in the inner core of the vesicles (Au-LAHP-vDOX). Upon irradiation, the in situ formation of hydroxyl radicals from LAHP molecules triggers the internal oxidation of PPS from being hydrophobic to hydrophilic, leading to degradation of the vesicles and burst release of cargo drugs. In this manner, synchronous chemoradiation showed impressive anticancer efficacy both in vitro and in a subcutaneous mouse tumor model by one-dose injection and one-time irradiation.

Antitumor Activity of a Unique Polymer That Incorporates a Fluorescent Self-Assembled Metallacycle.

Despite the well-known anticancer activity of mono- and multinuclear platinum complexes, studies of the antitumor performances of platinum-based supramolecular coordination complexes are rare. Herein, we report on the synthesis of a four-armed amphiphilic copolymer, Pt-PAZMB-b-POEGMA, containing a metallacycle M, in which the tetraphenylethene derivative acts as an aggregation-induced emissive fluorescent probe for live cell imaging and the 3,6-bis[trans-Pt(PEt3)2]phenanthrene (PhenPt) is an anticancer drug. This copolymer was further self-assembled into nanoparticles of different sizes and vesicles depending upon the experimental conditions. The impacts of the morphology and size of the assemblies on their endocytic pathways, uptake rates, internalization amounts, and cytotoxicities were investigated. The self-assemblies were further employed to encapsulate doxorubicin (DOX) to achieve a synergistic anticancer effect. Controlled drug release was also realized via amphiphilicity changes and was driven by a glutathione-induced cascade elimination reaction. The DOX-loaded nanoparticles of around 50 nm in size exhibited an excellent antitumor performance as well as a low systemic toxicity, due to an enhanced permeability and retention effect.

Double-Layered Plasmonic-Magnetic Vesicles by Self-Assembly of Janus Amphiphilic Gold-Iron(II,III) Oxide Nanoparticles.

Janus nanoparticles (JNPs) offer unique features, including the precisely controlled distribution of compositions, surface charges, dipole moments, modular and combined functionalities, which enable excellent applications that are unavailable to their symmetrical counterparts. Assemblies of NPs exhibit coupled optical, electronic and magnetic properties that are different from single NPs. Herein, we report a new class of double-layered plasmonic-magnetic vesicle assembled from Janus amphiphilic Au-Fe3 O4 NPs grafted with polymer brushes of different hydrophilicity on Au and Fe3 O4 surfaces separately. Like liposomes, the vesicle shell is composed of two layers of Au-Fe3 O4 NPs in opposite direction, and the orientation of Au or Fe3 O4 in the shell can be well controlled by exploiting the amphiphilic property of the two types of polymers.

Magneto-Plasmonic Janus Vesicles for Magnetic Field-Enhanced Photoacoustic and Magnetic Resonance Imaging of Tumors.

Magneto-plasmonic Janus vesicles (JVs) integrated with gold nanoparticles (AuNPs) and magnetic NPs (MNPs) were prepared asymmetrically in the membrane for in vivo cancer imaging. The hybrid JVs were produced by coassembling a mixture of hydrophobic MNPs, free amphiphilic block copolymers (BCPs), and AuNPs tethered with amphiphilic BCPs. Depending on the size and content of NPs, the JVs acquired spherical or hemispherical shapes. Among them, hemispherical JVs containing 50 nm AuNPs and 15 nm MNPs showed a strong absorption in the near-infrared (NIR) window and enhanced the transverse relaxation (T2 ) contrast effect, as a result of the ordering and dense packing of AuNPs and MNPs in the membrane. The magneto-plasmonic JVs were used as drug delivery vehicles, from which the release of a payload can be triggered by NIR light and the release rate can be modulated by a magnetic field. Moreover, the JVs were applied as imaging agents for in vivo bimodal photoacoustic (PA) and magnetic resonance (MR) imaging of tumors by intravenous injection. With an external magnetic field, the accumulation of the JVs in tumors was significantly increased, leading to a signal enhancement of approximately 2-3 times in the PA and MR imaging, compared with control groups without a magnetic field.

Targeting the activity of T cells by membrane surface redox regulation for cancer theranostics.

T cells play a determining role in the immunomodulation and prognostic evaluation of cancer treatments relying on immune activation. While specific biomarkers determine the population and distribution of T cells in tumours, the in situ activity of T cells is less studied. Here we designed T-cell-targeting fusogenic liposomes to regulate and quantify the activity of T cells by exploiting their surface redox status as a chemical target. The T-cell-targeting fusogenic liposomes equipped with 2,2,6,6-tetramethylpiperidine (TEMP) groups neutralize reactive oxygen species protecting T cells from oxidation-induced loss of activity. Meanwhile, the production of paramagnetic 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) radicals allows magnetic resonance imaging quantification of the T cell activity. In multiple mouse models, the T-cell-targeting fusogenic liposomes led to efficient tumour inhibition and to early prediction of radiotherapy outcomes. This study uses a chemical targeting strategy to measure the in situ activity of T cells for cancer theranostics and may provide further understanding on engineering T cells for cancer treatment.

Extensive sequence divergence between the reference genomes of Taraxacum kok-saghyz and Taraxacum mongolicum.

Plants belonging to the genus Taraxacum are widespread all over the world, which contain rubber-producing and non-rubber-producing species. However, the genomic basis underlying natural rubber (NR) biosynthesis still needs more investigation. Here, we presented high-quality genome assemblies of rubber-producing T. kok-saghyz TK1151 and non-rubber-producing T. mongolicum TM5. Comparative analyses uncovered a large number of genetic variations, including inversions, translocations, presence/absence variations, as well as considerable protein divergences between the two species. Two gene duplication events were found in these two Taraxacum species, including one common ancestral whole-genome triplication and one subsequent round of gene amplification. In genomes of both TK1151 and TM5, we identified the genes encoding for each step in the NR biosynthesis pathway and found that the SRPP and CPT gene families have experienced a more obvious expansion in TK1151 compared to TM5. This study will have large-ranging implications for the mechanism of NR biosynthesis and genetic improvement of NR-producing crops.

Targeted scavenging of extracellular ROS relieves suppressive immunogenic cell death.

Immunogenic cell death (ICD) and tumour-infiltrating T lymphocytes are severely weakened by elevated reactive oxygen species (ROS) in the tumour microenvironment. It is therefore of critical importance to modulate the level of extracellular ROS for the reversal of immunosuppressive environment. Here, we present a tumour extracellular matrix (ECM) targeting ROS nanoscavenger masked by pH sensitive covalently crosslinked polyethylene glycol. The nanoscavenger anchors on the ECM to sweep away the ROS from tumour microenvironment to relieve the immunosuppressive ICD elicited by specific chemotherapy and prolong the survival of T cells for personalized cancer immunotherapy. In a breast cancer model, elimination of the ROS in tumour microenvironment elicited antitumour immunity and increased infiltration of T lymphocytes, resulting in highly potent antitumour effect. The study highlights a strategy to enhance the efficacy of cancer immunotherapy by scavenging extracellular ROS using advanced nanomaterials.

Generic synthesis of small-sized hollow mesoporous organosilica nanoparticles for oxygen-independent X-ray-activated synergistic therapy.

The success of radiotherapy relies on tumor-specific delivery of radiosensitizers to attenuate hypoxia resistance. Here we report an ammonia-assisted hot water etching strategy for the generic synthesis of a library of small-sized (sub-50 nm) hollow mesoporous organosilica nanoparticles (HMONs) with mono, double, triple, and even quadruple framework hybridization of diverse organic moieties by changing only the introduced bissilylated organosilica precursors. The biodegradable thioether-hybridized HMONs are chosen for efficient co-delivery of tert-butyl hydroperoxide (TBHP) and iron pentacarbonyl (Fe(CO)5). Distinct from conventional RT, radiodynamic therapy (RDT) is developed by taking advantage of X-ray-activated peroxy bond cleavage within TBHP to generate •OH, which can further attack Fe(CO)5 to release CO molecules for gas therapy. Detailed in vitro and in vivo studies reveal the X-ray-activated cascaded release of •OH and CO molecules from TBHP/Fe(CO)5 co-loaded PEGylated HMONs without reliance on oxygen, which brings about remarkable destructive effects against both normoxic and hypoxic cancers.

Cooperation of endogenous and exogenous reactive oxygen species induced by zinc peroxide nanoparticles to enhance oxidative stress-based cancer therapy.

Reactive oxygen species (ROS)-generating anticancer agents can act through two different mechanisms: (i) elevation of endogenous ROS production in mitochondria, or (ii) formation/delivery of exogenous ROS within cells. However, there is a lack of research on the development of ROS-generating nanosystems that combine endogenous and exogenous ROS to enhance oxidative stress-mediated cancer cell death. Methods: A ROS-generating agent based on polymer-modified zinc peroxide nanoparticles (ZnO2 NPs) was presented, which simultaneously delivered exogenous H2O2 and Zn2+ capable of amplifying endogenous ROS production for synergistic cancer therapy. Results: After internalization into tumor cells, ZnO2 NPs underwent decomposition in response to mild acidic pH, resulting in controlled release of H2O2 and Zn2+. Intriguingly, Zn2+ could increase the production of mitochondrial O2·- and H2O2 by inhibiting the electron transport chain, and thus exerted anticancer effect in a synergistic manner with the exogenously released H2O2 to promote cancer cell killing. Furthermore, ZnO2 NPs were doped with manganese via cation exchange, making them an activatable magnetic resonance imaging contrast agent. Conclusion: This study establishes a ZnO2-based theranostic nanoplatform which achieves enhanced oxidative damage to cancer cells by a two-pronged approach of combining endogenous and exogenous ROS.

Gadolinium Metallofullerene-Polypyrrole Nanoparticles for Activatable Dual-Modal Imaging-Guided Photothermal Therapy.

Accurate diagnosis of tumor is promising to guide photothermal therapy (PTT) for efficacious tumor ablation with minimal damage to healthy tissues. Here, we report an activatable dual-modal imaging agent, which is based on PEGylated-gadolinium metallofullerene-polypyrrole nanoparticle (PEG-GMF-PPy NP) for imaging-guided PTT. A contrast agent (gadolinium metallofullerene, GMF) with excellent magnetic resonance imaging (MRI) performance and an ultra-pH-responsive polymer (PEG-PC7A) are successively modified to the surface of photothermal agent (PPy NP). The prepared PEG-GMF-PPy NPs show strong absorption in the near-infrared (NIR) region, so they can be utilized for photoacoustic imaging. Furthermore, in a tumor extracellular environment, the PEG-GMF-PPy NPs can achieve pH-enhanced MRI because of the hydrophobic-to-hydrophilic conversion of the PC7A. Upon accurate diagnosis-guided NIR laser irradiation, excellent tumor ablation effect is achieved. The results suggest that the PEG-GMF-PPy NPs are promising agents for activatable imaging-guided PTT.

Self-Assembly of Semiconducting-Plasmonic Gold Nanoparticles with Enhanced Optical Property for Photoacoustic Imaging and Photothermal Therapy.

Although various noble metal and semiconducting molecules have been developed as photoacoustic (PA) agents, the use of semiconducting polymer-metal nanoparticle hybrid materials to enhance PA signal has not been explored. A novel semiconducting-plasmonic nanovesicle was fabricated by self-assembly of semiconducting poly(perylene diimide) (PPDI) and poly(ethylene glycol (PEG) tethered gold nanoparticles (Au@PPDI/PEG). A highly localized and strongly enhanced electromagnetic (EM) field is distributed between adjacent gold nanoparticles in the vesicular shell, where the absorbing collapsed PPDI is present. Significantly, the EM field in turn enhances the light absorption efficiency of PPDI, leading to a much greater photothermal effect and a stronger photoacoustic signal compared to PDI nanoparticle or gold nanovesicle alone. The optical property of the hybrid vesicle can be further tailored by controlling the ratio of PPDI and gold nanoparticle as well as the adjustable interparticle distance of gold nanoparticles localized in the vesicular shell. In vivo imaging and therapeutic evaluation demonstrated that the hybrid vesicle is an excellent probe for cancer theranostics.

Core-Satellite Polydopamine-Gadolinium-Metallofullerene Nanotheranostics for Multimodal Imaging Guided Combination Cancer Therapy.

Integration of magnetic resonance imaging (MRI) and other imaging modalities is promising to furnish complementary information for accurate cancer diagnosis and imaging-guided therapy. However, most gadolinium (Gd)-chelator MR contrast agents are limited by their relatively low relaxivity and high risk of released-Gd-ions-associated toxicity. Herein, a radionuclide-64 Cu-labeled doxorubicin-loaded polydopamine (PDA)-gadolinium-metallofullerene core-satellite nanotheranostic agent (denoted as CDPGM) is developed for MR/photoacoustic (PA)/positron emission tomography (PET) multimodal imaging-guided combination cancer therapy. In this system, the near-infrared (NIR)-absorbing PDA acts as a platform for the assembly of different moieties; Gd3 N@C80 , a kind of gadolinium metallofullerene with three Gd ions in one carbon cage, acts as a satellite anchoring on the surface of PDA. The as-prepared CDPGM NPs show good biocompatibility, strong NIR absorption, high relaxivity (r 1 = 14.06 mM-1 s-1 ), low risk of release of Gd ions, and NIR-triggered drug release. In vivo MR/PA/PET multimodal imaging confirms effective tumor accumulation of the CDPGM NPs. Moreover, upon NIR laser irradiation, the tumor is completely eliminated with combined chemo-photothermal therapy. These results suggest that the CDPGM NPs hold great promise for cancer theranostics.

Rational Design of Branched Nanoporous Gold Nanoshells with Enhanced Physico-Optical Properties for Optical Imaging and Cancer Therapy.

Reported procedures on the synthesis of gold nanoshells with smooth surfaces have merely demonstrated efficient control of shell thickness and particle size, yet no branch and nanoporous features on the nanoshell have been implemented to date. Herein, we demonstrate the ability to control the roughness and nanoscale porosity of gold nanoshells by using redox-active polymer poly(vinylphenol)-b-(styrene) nanoparticles as reducing agent and template. The porosity and size of the branches on this branched nanoporous gold nanoshell (BAuNSP) material can be facilely adjusted by control of the reaction speed or the reaction time between the redox-active polymer nanoparticles and gold ions (Au3+). Due to the strong reduction ability of the redox-active polymer, the yield of BAuNSP was virtually 100%. By taking advantage of the sharp branches and nanoporous features, BAuNSP exhibited greatly enhanced physico-optical properties, including photothermal effect, surface-enhanced Raman scattering (SERS), and photoacoustic (PA) signals. The photothermal conversion efficiency can reach as high as 75.5%, which is greater than most gold nanocrystals. Furthermore, the nanoporous nature of the shells allows for effective drug loading and controlled drug release. The thermoresponsive polymer coated on the BAuNSP surface serves as a gate keeper, governing the drug release behavior through photothermal heating. Positron emission tomography imaging demonstrated a high passive tumor accumulation of 64Cu-labeled BAuNSP. The strong SERS signal generated by the SERS-active BAuNSP in vivo, accompanied by enhanced PA signals in the tumor region, provide significant tumor information, including size, morphology, position, and boundaries between tumor and healthy tissues. In vivo tumor therapy experiments demonstrated a highly synergistic chemo-photothermal therapy effect of drug-loaded BAuNSPs, guided by three modes of optical imaging.

Multifunctional Theranostic Nanoparticles Based on Exceedingly Small Magnetic Iron Oxide Nanoparticles for T1-Weighted Magnetic Resonance Imaging and Chemotherapy.

The recently emerged exceedingly small magnetic iron oxide nanoparticles (ES-MIONs) (<5 nm) are promising T1-weighted contrast agents for magnetic resonance imaging (MRI) due to their good biocompatibility compared with Gd-chelates. However, the best particle size of ES-MIONs for T1 imaging is still unknown because the synthesis of ES-MIONs with precise size control to clarify the relationship between the r1 (or r2/r1) and the particle size remains a challenge. In this study, we synthesized ES-MIONs with seven different sizes below 5 nm and found that 3.6 nm is the best particle size for ES-MIONs to be utilized as T1-weighted MR contrast agent. To enhance tumor targetability of theranostic nanoparticles and reduce the nonspecific uptake of nanoparticles by normal healthy cells, we constructed a drug delivery system based on the 3.6 nm ES-MIONs for T1-weighted tumor imaging and chemotherapy. The laser scanning confocal microscopy (LSCM) and flow cytometry analysis results demonstrate that our strategy of precise targeting via exposure or hiding of the targeting ligand RGD2 on demand is feasible. The MR imaging and chemotherapy results on the cancer cells and tumor-bearing mice reinforce that our DOX@ES-MION3@RGD2@mPEG3 nanoparticles are promising for high-resolution T1-weighted MR imaging and precise chemotherapy of tumors.

Gadolinium embedded iron oxide nanoclusters as T1-T2 dual-modal MRI-visible vectors for safe and efficient siRNA delivery.

This report illustrates a new strategy of designing a T1-T2 dual-modal magnetic resonance imaging (MRI)-visible vector for siRNA delivery and MRI. Hydrophobic gadolinium embedded iron oxide (GdIO) nanocrystals are self-assembled into nanoclusters in the water phase with the help of stearic acid modified low molecular weight polyethylenimine (stPEI). The resulting water-dispersible GdIO-stPEI nanoclusters possess good stability, monodispersity with narrow size distribution and competitive T1-T2 dual-modal MR imaging properties. The nanocomposite system is capable of binding and delivering siRNA for knockdown of a gene of interest while maintaining its magnetic properties and biocompatibility. This new gadolinium embedded iron oxide nanocluster provides an important platform for safe and efficient gene delivery with non-invasive T1-T2 dual-modal MRI monitoring capability.